Biosafety and product release testing issues relevant to replication-competent oncolytic viruses

Abstract

Replication competent oncolytic viruses, like other biological products, are at risk from contamination by bacteria, fungi, mycoplasma and viruses that must be eliminated from the final product. This article reviews the regulatory guidance for the manufacture and testing for oncolytic virus products. A testing strategy covering the testing of cell lines, virus banks, virus harvests and purified product is described.

Production of Clostridium difficile toxin in a medium totally free of both animal and dairy proteins or digests

“…Such preparations might yield toxoid containing undesirable contaminants such as the prion causing bovine spongiform encephalopathy (BSE; Mad Cow Disease) or antigenic peptides that stimulate anaphylactic reactions and other undesirable immune reactions in immunized hosts (23). When non-animal/ non-dairy peptones were used by others, such as phytone or yeast extract, the toxin titers were markedly lower, that is, 12.5 or 25% respectively of the titer with animal/dairy products.…”

Moving oncolytic viruses into the clinic: clinical-grade production, purification, and characterization of diverse oncolytic viruses

“…Particular attention should be directed toward a detailed characterization of a stable good manufacturing practice (GMP) process, including the establishment of a master cell bank and a master seed virus and the development of sophisticated release assays. 14–16 Thus, it is advisable that developers of oncolytic Ads contact local regulatory authorities at an early time point to discuss these issues.…”

“… 18 An additional challenge is a consistent surveillance of master cell bank and master seed virus used in the production of oncolytic Ads that included tests for the cellular identity and the absence of any adventitious contaminants, such as mycoplasma and bovine/porcine viruses. 14 …”

The nitroreductase prodrug SN 28343 enhances the potency of systemically administered armed oncolytic adenovirus ONYX-411NTR

“…[29][30][31] Prodrug-activating genes ('suicide genes') are attractive candidates for 'arming' CRAds since augmentation of viral activity is conditional on prodrug administration, thereby allaying biosafety concerns associated with directly toxic gene products. 32 This approach, termed virus-directed enzyme-prodrug therapy (VDEPT), utilizes deactivated precursors of cytotoxic agents that require metabolism to exert their antiproliferative effects. 33,34 The most clinical advanced enzyme/prodrug combinations for VDEPT are Escherichia coli cytosine deaminase (CD) for conversion of 5-fluorocytosine to the antineoplastic agent 5-fluorouracil, and herpes simplex virus thymidine kinase (TK) for activation of the prodrug gancyclovir.…”